Molecular Targets for Combined Therapeutic Strategies to Limit Glioblastoma Cell Migration and Invasion

Abstract

The highly invasive nature of glioblastoma imposes poor prospects for patient survival. Molecular evidence indicates glioblastoma cells undergo an intriguing expansion of phenotypic properties to include neuron-like signaling using excitable membrane ion channels and synaptic proteins, augmenting survival and motility. Neurotransmitter receptors, membrane signaling, excitatory receptors, and Ca 2+ responses are important candidates for the design of customized treatments for cancers within the heterogeneous central nervous system. Relatively few published studies of glioblastoma multiforme (GBM) have evaluated pharmacological agents targeted to signaling pathways in limiting cancer cell motility. Transcriptomic analyses here identified classes of ion channels, ionotropic receptors, and synaptic proteins that are enriched in human glioblastoma biopsy samples. The pattern of GBM-enriched gene expression points to a major role for glutamate signaling. However, the predominant role of AMPA receptors in fast excitatory signaling throughout the central nervous system raises a challenge on how to target inhibitors selectively to cancer cells while maintaining tolerability. This review critically evaluates a panel of ligand-and voltage-gated ion channels and synaptic proteins upregulated in GBM, and the evidence for their potential roles in the pathological disease progress. Evidence suggests combinations of therapies could be more effective than single agents alone. Natural plant products used in traditional medicines for the treatment of glioblastoma contain flavonoids, terpenoids, polyphenols, epigallocatechin gallate, quinones, and saponins, which might serendipitously include agents that modulate some classes of signaling compounds highlighted in this review. New therapeutic strategies are likely to exploit evidence-based combinations of selected agents, each at a low dose, to create new cancer cell-specific therapeutics. A BFIGURE 1 | Illustration of a sample distribution of published glioblastoma studies suggesting less than 3% combine three themes (inhibitor, proliferation, motility). Venn diagram (A) summarizing the numbers of published articles on glioblastoma, with key words linked to inhibition,

Validation of the Functions and Prognostic Values of Synapse Associated Proteins in Lower-Grade Glioma

“…Both in vitro and invivo, EC cells showed its tropism toward DRG neurons and neuron ber which implied that glutamate receptor signal and neuron-tumor interaction play a signi cant role in EC growth (25). Moreover, in the central nervous system, previous studies demonstrated that the generation of synapse and glutamate receptor signals were linked to the progression of high-grade glioma and breast tumor patients, which corroborates with our results of LGG patients (12,(26)(27)(28).…”

Cannabigerol Is a Potential Therapeutic Agent in a Novel Combined Therapy for Glioblastoma

“…GB is a very specific type of cancer, as its metastases have rarely been found in other organs, unlike most tumours of epithelial origin that frequently metastasize to the brain [ 55 ]. This seems paradoxical, as GB cells are highly invasive and aggressively infiltrate far into the brain parenchyma, a very early event during GB growth [ 4 , 56 ]. Moreover, updated standard GB treatment protocols [ 7 ] may induce the expression of mesenchymal GB subtypes associated with higher invasiveness [ 57 ].…”

“…It is characterized by distinct histological features such as necrosis, vascular proliferation, and pleomorphism [ 1 ]. Its poor prognosis is due to two major reasons: (1) the diffuse infiltration of highly invasive individual GB cells into the brain parenchyma [ 2 , 3 , 4 ], which prevents complete tumour resection, and (2) the high resilience of brain tumour-initiating cells, i.e., glioblastoma stem cells (GSCs). These cells most likely evolve from normal neural stem cells or by dedifferentiation (reverse differentiation) of any of their progenitors along with the accumulation of oncogenic mutations during gliomagenesis [ 5 , 6 , 7 ].…”

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

“…The discovery of plant-derived bioactive compounds as novel therapeutics may provide therapeutic advantages in HGG research ( Figure 3 , Table 8 ). Around 60 percent of commercially available clinically approved anti-cancer medications are derived from medicinal plants [ 339 , 340 ]. Their multitarget, high selectivity against cancer cells, capable of reducing multidrug chemoresistance, inexpensive and marginal side effects make them valuable potential therapeutics, especially when combined with current therapy advancement [ 341 ].…”